1. To identify key differentiation genes and characterize their molecular mechanisms of action A. Identification, Cloning and Characterization of CASZ1, the human homolog of the drosophila neural fate determination gene castor (dCas). We identified that there are 2 predominant isoforms of CASZ1;hCas11 (now referred to as CASZ1a), which has 11 zinc fingers, and hCas5 (CASZ1b) which has 5 zinc fingers. Total CASZ1 mRNA levels dramatically increased upon induction of differentiation in neuron and muscle cell models. The study of CASZ1 is warranted because it;1) maps to chromosome 1p36.22 a region lost in almost 98% of NB tumors with 1p36 LOH;2) was a highly evolutionarily conserved neural fate determination gene;3) has not been functionally studied in mammalian model systems;4) is regulated during NB cell differentiation and 5) is expressed at high levels in primary tumors of NB patients with good overall survival (p=0.0009). Using isogenic NB models with TET-inducible expression of CASZ1a,or CASZ1b we determined that CASZ1 functions to suppress NB tumor cell growth, induce differentiation and inhibit motility in vitro. More importantly, CASZ1 suppresses NB tumor xenograft growth in vivo . CASZ1 is capable of suppressing or inhibiting growth in tumor cells with 1pLOH, MYCN amplification as well as non-MYCN amplified tumor cells. These studies indicates that CASZ1 functions as a 1p36 tumor suppressor gene in neuroblastoma. Current studies are aimed at delineating how the structure of CASZ1 mediates its function and the signaling pathways CASZ1 utilizes to mediate its tumor suppressive function. We are using biochemical as well as gene-targeting approaches in cell and animal model systems to assess CASZ1 function.
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